Flat-Fixed Dosing of Irinotecan

Jong, Floris A. de; Mathijssen, Ron H.J.; Xie, Ruiqin; Verweij, Jaap; Sparreboom, Alex

doi:10.1158/1078-0432.ccr-03-0591

Cited by 50 publications

(38 citation statements)

References 18 publications

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“…As a result, the interindividual pharmacokinetic variability of irinotecan and its active metabolite SN-38 were 19% to 25% lower in the equation-based dosing group, whereas the dose range was substantially broader in this group. In line with the known association between irinotecan pharmacokinetics and drug-related toxicities (5,8,18), a >4-fold reduction of severe myelosuppression was observed in the equationbased dosing group as compared with the other group.…”

Section: Discussionsupporting

confidence: 65%

“…The conventional dose calculation of irinotecan is based on an individual's body surface area (BSA), although this approach does not result in reduced pharmacokinetic variability ( Fig. 2A) compared with a flat-fixed dose (7,8). New dosing strategies that take the pharmacologic profile of irinotecan in the individual patient into account could potentially replace BSA-based dosing, if this would lead to a reduction in the pharmacokinetic variability.…”

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confidence: 99%

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A CYP3A4 Phenotype–Based Dosing Algorithm for Individualized Treatment of Irinotecan

Bol

Mathijssen

Creemers

et al. 2010

Clinical Cancer Research

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Purpose: Irinotecan, the prodrug of SN-38, is extensively metabolized by cytochrome P450-3A4 (CYP3A4). A randomized trial was done to assess the utility of an algorithm for individualized irinotecan dose calculation based on a priori CYP3A4 activity measurements by the midazolam clearance test.Experimental Design: Patients were randomized to receive irinotecan at a conventional dose level of 350 mg/m 2 (group A) or doses based on an equation consisting of midazolam clearance, γ-glutamyltransferase, and height (group B). Pharmacokinetics and toxicities were obtained during the first treatment course.Results: Demographics of 40 evaluable cancer patients were balanced between both groups, including UGT1A1*28 genotype and smoking status. The absolute dose of irinotecan ranged from 480 to 800 mg in group A and 380 to 1,060 mg in group B. The mean absolute dose and area under the curve of irinotecan and SN-38 were not significantly different in either group (P > 0.18). In group B, the interindividual variability in the area under the curve of irinotecan and SN-38 was reduced by 19% and 25%, respectively (P > 0.22). Compared with group A, the incidence of grades 3 to 4 neutropenia was >4-fold lower in group B (45 versus 10%; P = 0.013). The incidence of grades 3 to 4 diarrhea was equal in both groups (10%).Conclusions: Incorporation of CYP3A4 phenotyping in dose calculation resulted in an improved predictability of the pharmacokinetic and toxicity profile of irinotecan, thereby lowering the incidence of severe neutropenia. In combination with UGT1A1*28 genotyping, CYP3A4 phenotype determination should be explored further as a strategy for the individualization of irinotecan treatment. Clin Cancer Res; 16(2); 736-42. ©2010 AACR.

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Section: Discussionsupporting

confidence: 65%

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confidence: 99%

A CYP3A4 Phenotype–Based Dosing Algorithm for Individualized Treatment of Irinotecan

Bol

Mathijssen

Creemers

et al. 2010

Clinical Cancer Research

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“…The interindividual variability in irinotecan and SN-38 pharmacokinetic parameters is large and has been associated with variation in its clinical outcome and toxicity profiles (25). Previous investigations have demonstrated that body surface area is an unimportant factor in explaining this variability (29). The interindividual variability in SN-38 pharmacokinetics is more likely related to a host of other factors, including hepatic function (30) and use of concomitant medication (31) in addition to multiple polymorphic pathways involved in the excretion and biotransformation of irinotecan.…”

Section: Discussionmentioning

confidence: 99%

ABCG2 Pharmacogenetics

Jong

Marsh

Mathijssen

et al. 2004

Clinical Cancer Research

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Purpose: The ATP-binding cassette transporter ABCG2 (breast cancer resistance protein) is an efflux protein that plays a role in host detoxification of various xenobiotic substrates, including the irinotecan metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). The ABCG2 421C>A polymorphism has been associated with reduced protein expression and altered function in vitro. The aim of this study was to evaluate the ethnic distribution and potential functional consequence of the ABCG2 421C>A genotype in cancer patients treated with irinotecan.Experimental Design: ABCG2 genotyping was performed using Pyrosequencing on DNA from 88 American Caucasians, 94 African Americans, 938 Africans, and 95 Han Chinese, as well as in 84 European Caucasian patients treated with irinotecan undergoing additional blood sampling for pharmacokinetic studies.Results: Significant differences in allele frequencies were observed between the given world populations (P < 0.001), the variant allele being most common in the Han Chinese population with a frequency as high as 34%. The mean area under the curve of irinotecan and SN-38 were 19,851 and 639 ng ؋ hour/mL, respectively. The frequency of the variant allele (10.7%) was in line with results in American Caucasians. No significant changes in irinotecan pharmacokinetics were observed in relation to the ABCG2 421C>A genotype, although one of two homozygous variant allele carriers showed extensive accumulation of SN-38 and SN-38 glucuronide.Conclusions: The ABCG2 421C>A polymorphism appears to play a limited role in the disposition of irinotecan in European Caucasians. It is likely that the contribution of this genetic variant is obscured by a functional role of other polymorphic proteins.

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“…Patients who were treated with single-agent irinotecan once every 3 weeks over 90 minutes at a dose of 350 mg/m 2 , its 600 mg flat-fixed (irrespective of BSA) dose equivalent [32,33], or at a dose that was based on cytochrome P450 (CYP)3A4 phenotyping [34] were studied during their first treatment course. Premedication consisted of dexamethasone and granisetron.…”

Section: Patients and Treatmentmentioning

confidence: 99%

Effects of Mannose-Binding Lectin Polymorphisms on Irinotecan-Induced Febrile Neutropenia

Bol

Jong

Schaik³

et al. 2010

The Oncologist

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Objective. Mannose-binding lectin (MBL) is important in the innate immune response. MBL2 gene polymorphisms affect MBL expression, and genotypes yielding low MBL levels have been associated with an elevated risk for infections in hematological cancer patients undergoing chemotherapy. However, these reported associations are inconsistent, and data on patients with solid tumors are lacking. Here, we investigated the effects of MBL2 genotypes on irinotecan-induced febrile neutropenia in patients with solid tumors.Patients and Methods. Irinotecan-treated patients were genotyped for the MBL2 gene. Two promoter (؊550 H/L and ؊221 X/Y) and three exon polymorphisms (52 A/D, 54 A/B, and 57 A/C) were determined, together with known risk factors for irinotecan-induced toxicity. Neutropenia and febrile neutropenia were recorded during the first course.Results

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Flat-Fixed Dosing of Irinotecan

Cited by 50 publications

References 18 publications

A CYP3A4 Phenotype–Based Dosing Algorithm for Individualized Treatment of Irinotecan

A CYP3A4 Phenotype–Based Dosing Algorithm for Individualized Treatment of Irinotecan

ABCG2 Pharmacogenetics

Effects of Mannose-Binding Lectin Polymorphisms on Irinotecan-Induced Febrile Neutropenia

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